Dorsal raphe nuclear stimulation of SCN serotonin release and circadian phase-resetting

Serotonin (5-HT) is strongly implicated in the regulation of mammalian circ adian rhythms. However, little is known of the functional relationship betw een the circadian clock located in the suprachiasmatic nucleus (SCN) and it s source of serotonergic innervation, the midbrain raphe nuclei. In previou s studies, we reported that electrical stimulation of the dorsal or median raphe nuclei (DRN and MRN, respectively) induced 5-HT release in the SCN. N otably, DRN- but not MRN-stimulated 5-HT release was blocked by the 5-HT1,2 ,7 antagonist, metergoline, suggesting that the DRN signals to the SCN indi rectly via the activation of a 5-HT-responsive multisynaptic pathway. In th e present study, pretreatment with the 5-HT2,7 antagonist, ritanserin, also significantly inhibited DRN-electrically stimulated SCN 5-HT release. Howe ver, pretreatment with the 5-HT1A antagonist, NAN-190, or the 5-HT2 antagon ists ketanserin and cinanserin had Little suppressive effect on this DRN-st imulated 5-HT release. In complementary behavioral trials, electrical stimu lation of the DRN during subjective midday caused a 1.3-h advance in the fr ee-running circadian activity rhythm under constant darkness, which was inh ibited by metergoline. Collectively, these results are evidence that: (1) D RN-stimulated 5-HT release in the SCN requires the activation of an interme diate target with receptors having 5-HT7 pharmacological characteristics; ( 2) electrical stimulation of the DRN induces phase-resetting of the circadi an activity rhythm; and (3) activation of 5-HT receptors is necessary for t his DRN-stimulated circadian phase-resetting. In view of the dynamic change s in DRN neuronal activity incumbent with the daily sleep-activity cycle, a nd its functional linkages to the SCN and intergeniculate leaflet, the DRN could serve to provide behavioral/arousal state information to various site s comprising the brain circadian system. (C) 2000 Published by Elsevier Sci ence B.V. All rights reserved.